Melanocortin-4 Receptor Pathway Research Articles

12497 Stage 1 Results Of The Phase 2 Daybreak Trial Assessing Setmelanotide In Patients With Early-onset, Severe Obesity And Hyperphagia Who Carried A Confirmed Variant Related To The Melanocortin-4 Receptor Pathway

Abstract Disclosure: G. Ortiz: Speaker; Self; Rhythm Pharmaceuticals, Inc. S.B. Ten: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Speaker; Self; Rhythm Pharmaceuticals, Inc. W. Herring: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc, Novo Nordisk. O. Pinhas-Hamiel: None. E.A. Oral: Consulting Fee; Self; Rhythm Pharmaceuticals, Inc., Akcea Therapeutics, Ionis Pharmaceuticals Inc., Morphic Medical, Fractyl Laboratories, Regeneron Pharmaceuticals, Amryt Pharmaceuticals (now Chiesi), Third Rock Ventures, Rejuvenate Bio, NIDDK. Other; Self; Has patents for use of metreleptin in lipodystrophy and recombinant leptin or analogues in NASH. N. Rosano: Consulting Fee; Self; Novo Nordisk. Speaker; Self; Rhythm Pharmaceuticals, Inc. D. Koren: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. H. Lee: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. J. Garrison: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. O. Ohayon: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. P. Sleiman: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. M. Wabitsch: Consulting Fee; Self; Rhythm Pharmaceuticals, Inc.. Speaker; Self; Rhythm Pharmaceuticals, Inc.. Other; Self; Rhythm Pharmaceuticals, Inc. E. van den Akker: Speaker; Self; Federatie Medisch Specialisten, Stichting Kwaliteitsgelden Medisch Specialisten, Medialane TV, Pfizer, Inc.. Other; Self; Nederlandse Hartstichting/ZonMW, Stichting Erasmus Trustfonds, Rhythm Pharmaceuticals, Inc. J. Argente: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Speaker; Self; Rhythm Pharmaceuticals, Inc.. I. Farooqi: None. Background: DAYBREAK (NCT04963231) was designed to evaluate setmelanotide in individuals who carried a confirmed variant in ≥1 of 31 genes with strong or very strong relevance to the melanocortin-4 receptor (MC4R) pathway, which regulates energy balance and satiety. Methods: DAYBREAK is a 2-stage, double-blind, placebo-controlled trial conducted at 37 sites across 8 countries. Individuals aged 6 to 65 years with body mass index (BMI) ≥40 kg/m2 (aged ≥18 years) or ≥97th percentile (aged ≥6 to <18 years) and hyperphagia who carried variants classified as uncertain significance (VUS), likely pathogenic, or pathogenic according to the American College of Medical Genetics (ACMG) criteria in ≥1 of the 31 genes were eligible. Individuals with ≥5% BMI reduction from baseline (ie, responders) at the end of the 16-week, open-label run-in period (Stage 1) were eligible to enter a 24-week, double-blind, randomized, placebo-controlled period (Stage 2). The primary endpoint of Stage 1 was the proportion of responders per gene cohort at the end of the Stage. Results: A total of 164 individuals were enrolled; 100 patients who completed Stage 1 and 12 who discontinued treatment within a prespecified 2 weeks before the end of Stage 1 were included in the completers analysis. Participants were divided into 15 gene cohorts; of 7 cohorts with ≥5 patients, 6 (SEMA3[A-G], PLXNA[1-4], PHIP, TBX3, MAGEL2, and SIM1) showed potential setmelanotide efficacy (KSR2 did not). Response rates across cohorts (range, 25.0%-56.3%), intracohort response magnitudes (percent BMI change from baseline to Week 16; range, −6.4% to −4.0%), and intracohort variant types varied. While response rate was highest in the PHIP cohort (56.3% of the full cohort and 69.2% of completers), ≥1 patient per cohort achieved ≥10% BMI reduction. Because ∼80% of VUS are eventually reclassified to benign or likely benign, the inclusion of VUS may have contributed to response variability. An ad hoc analysis showed an increased response rate with updated versus starting ACMG variant classification. Overall, 49 responders across 6 gene cohorts were randomized into Stage 2. Setmelanotide was well tolerated with no new safety concerns. Conclusions: DAYBREAK Stage 1 identified 6 additional genes or gene families in the MC4R pathway that respond to setmelanotide. Response was associated with predicted variant pathogenicity, allowing for further refinement of patient selection. Stage 2 results will further elucidate Stage 1 findings. Presentation: 6/3/2024

Cardiometabolic Risk Markers in Children With Obesity and Variants in MC4R Pathway-related Genes.

Variants in melanocortin 4 receptor (MC4R) pathway-related genes have been associated with obesity. The association of these variants with cardiometabolic parameters are not fully known. We compared the severity of obesity and cardiometabolic risk markers in children with MC4R pathway-related clinically reported genetic variants relative to children without these variants. A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the MC4R pathway, and the remaining 65 patients did not have reported MC4R pathway-related variants. Among the MC4R-related variants, PCSK1 risk alleles were most common, reported in 15 children (14%). The maximum body mass index percent of the 95th percentile was not different between groups (P = .116). Low-density lipoprotein cholesterol (LDL-C) was not different between groups (P = .132). However, subgroup analysis demonstrated higher LDL cholesterol in children with the PCSK1 c.661A>G risk allele relative to those with MC4R-related variant of uncertain significance (P = .047), negative genetic testing (P = .012), and those with non-MC4R related variants (P = .048). The blood pressure, fasting glucose, hemoglobin A1C, total cholesterol, alanine transaminase, and high-density lipoprotein cholesterol were not different between groups. Variants in the MC4R pathway-related genes were not associated with severity of obesity and cardiometabolic risk markers except for the c.661A>G PCSK1 risk allele, which was associated with higher LDL-C levels.

Investigation of setmelanotide, an MC4R agonist, for obesity in individuals with Smith-Magenis syndrome

BackgroundSmith Magenis Syndrome (SMS) is a rare genetic disorder caused by RAI1 haploinsufficiency. Obesity in people with SMS is believed partially due to dysfunction of the proximal melanocortin 4 receptor (MC4R) pathway. We therefore studied effects of treatment with the MC4R agonist setmelanotide on obesity and hunger, as well as metabolic, cardiac and safety, in individuals with SMS. MethodsPeople with SMS received once-daily setmelanotide injections, with the dose titrated bi-weekly to a maximum of 3 mg over ∼1 month; and a full-dose treatment duration of 3mo. The primary outcome was percent change in body weight. Secondary outcomes included hunger, waist circumference, body composition, and safety. Results12 individuals, ages 11–39 y, enrolled and 10 completed the full-dose treatment phase. Mean percent change in body weight at end-treatment was − 0.28 % [(95 % CI, −2.1 % to 1.5 %; n = 12; P = 0.66]. Participants experienced a significant decrease in total cholesterol associated with a significant decrease in HDL-cholesterol and a trend for lower LDL-cholesterol. Self-reported hunger was reduced at end-treatment (p = 0.011). All participants reported adverse events (AEs), most commonly injection-site reactions and skin hyperpigmentation. No AEs led to withdrawal or death. ConclusionsIn this trial, setmelanotide did not significantly reduce body weight in participants with SMS. Participants reported significant differences in hunger, but such self-reports are difficult to interpret without a placebo-treated group. The changes in lipid profiles require further investigation. Results of this study do not suggest that dysfunction of the proximal MC4R pathway is the main etiology for obesity in people with SMS.

The melanocortin-4 receptor pathway and the emergence of precision medicine in obesity management.

Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical condition, obesity is an intricate disease with a multifactorial aetiology. Understanding the precise cause of obesity remains a challenge; nevertheless, there seems to be a complex interplay among biological, psychosocial and behavioural factors. Studies on the genetic factors of obesity have revealed several pathways in the brain that play a crucial role in food intake regulation. The best characterized pathway, thus far, is the leptin-melanocortin pathway, from which disruptions are responsible for the majority of monogenic obesity disorders. The effectiveness of conservative lifestyle interventions in addressing monogenic obesity has been limited. Therefore, it is crucial to complement the management strategy with pharmacological and surgical options. Emphasis has been placed on developing drugs aimed at replacing the absent signals, with the goal of restoring the pathway. In both monogenic and polygenic forms of obesity, outcomes differ across various interventions, likely due to the multifaceted nature of the disease. This underscores the need to explore alternative therapeutic strategies that can mitigate this heterogeneity. Precision medicine can be regarded as a powerful tool that can address this concern, as it values the understanding of the underlying abnormality triggering the disease and provides a tailored treatment accordingly. This would assist in optimizing outcomes of the current therapeutic approaches and even aid in the development of novel treatments capable of more effectively managing the global obesity epidemic.

GRP78 acts as a cAMP/PKA signaling modulator through the MC4R pathway in porcine embryonic development.

Glucose-regulated protein 78 (GRP78) binds to and stabilizes melanocortin 4 receptor (MC4R), which activates protein kinase A (PKA) by regulating G proteins. GRP78 is primarily used as a marker for endoplasmic reticulum stress; however, its other functions have not been well studied. Therefore, in this study, we aimed to investigate the function of GRP78 during porcine embryonic development. The developmental quality of porcine embryos, expression of cell cycle proteins, and function of mitochondria were evaluated by inhibiting the function of GRP78. Porcine oocytes were activated to undergo parthenogenesis, and blastocysts were obtained after 7 days of invitro culture. GRP78 function was inhibited by adding 20 μM HA15 to the invitro culture medium. The inhibition in GRP78 function led to a decrease in G proteins release, which subsequently downregulated the cyclic adenosine monophosphate (cAMP)/PKA pathway. Ultimately, inhibition of GRP78 function induced the inhibition of CDK1 and cyclin B expression and disruption of the cell cycle. In addition, inhibition of GRP78 function regulated DRP1 and SIRT1 expression, resulting in mitochondrial dysfunction. This study provides new insights into the role of GRP78 in porcine embryonic development, particularly its involvement in the regulation of the MC4R pathway and downstream cAMP/PKA signaling. The results suggest that the inhibition of GRP78 function in porcine embryos by HA15 treatment may have negative effects on embryo quality and development. This study also demonstrated that GRP78 plays a crucial role in the functioning of MC4R, which releases the G protein during porcine embryonic development.

FRI048 Cardiometabolic Risk Markers In Children With Obesity And Variants In MC4R Pathway Related Genes

Abstract Disclosure: M. Salama: None. S. Kumar: None. F. Pinto e Vairo: None. R. Hentz: None. Objective: The association between disrupted melanocortin 4 receptor (MC4R) pathway function and childhood obesity is well established. Several variants in MC4R pathway related genes have been implicated to influence cardiometabolic parameters including lipid metabolism and glucose homeostasis. We compared the cardiometabolic risk markers in children with obesity and MC4R related clinically reported genetic variants relative to children with obesity and no MC4R related genetic variants. Methods: This was a retrospective case-control study conducted by chart review of children (age <18 years) with obesity who underwent a multi-gene panel testing for monogenic obesity between February 2020 and November 2022. Children were divided into two groups according to their genetic test results: The first group was of children with clinically reported variants (pathogenic, likely pathogenic, risk allele or variant of uncertain significance) within the MC4R pathway), and the second group was of children with no reported variants in the MC4R pathway (negative genetic testing or variants in non-MC4R related genes). Data on systolic and diastolic blood pressure percentiles, fasting lipid panel, fasting blood glucose, hemoglobin A1c and ALT were extracted. Tests for group differences were performed using the independent two-sample t-test, Wilcoxon rank-sum test, Chi-Square test, or Fisher’s exact test as appropriate for each variable type and test assumptions. Results: Data on a total of 91 children were reviewed. Mean age at testing was 11 years (SD: 4) and mean peak BMI% of the 95th percentile was 158 (SD: 28). 36 patients had clinically reported variants in the MC4R pathway, and 55 patients had no reported MC4R related variants. The blood pressure percentiles, fasting glucose, hemoglobin A1C, total cholesterol, high density lipoprotein cholesterol and low-density lipoprotein cholesterol were not different between both groups. Conclusion: In this pilot study, among children with obesity, variants in the MC4R pathway related genes were not associated with cardiometabolic risk markers. Larger studies are warranted to assess the correlation between MC4R pathway genes and cardiometabolic risk. Presentation: Friday, June 16, 2023

An evaluation of setmelanotide injection for chronic weight management in adult and pediatric patients with obesity due to Bardet–Biedl syndrome

ABSTRACT Introduction Bardet–Biedl Syndrome (BBS) is a rare, multisystemic ciliopathy with an incidence of obesity of 89%. Mutations in genes encoding BBS proteins are linked to reduced leptin sensitivity of hypothalamic POMC neurons and reduced activation of the melanocortin-4 receptor (MC4R) pathway due to deficient α-MSH production by hypothalamic POMC neurons. The MC4R pathway is involved in controlling body weight and energy metabolism, and its disruption is linked to hyperphagia and obesity. Setmelanotide is an MC4R agonist that counteracts deficiencies in the MC4R pathway of individuals with BBS. Areas covered Data from clinical trials were reviewed along with information available from setmelanotide’s approval for treatment of obesity in people ages ≥6y with a clinical diagnosis of BBS. Expert opinion Setmelanotide is available as a daily injectable that can be used for amelioration of obesity in people with Bardet–Biedl syndrome. Its cost is substantial, which may limit its use, but among those who respond, setmelanotide can reduce body mass dramatically and potentially improve comorbid conditions associated with obesity. Setmelanotide treatment has generally tolerable side effects, primarily injection site reactions and nausea/vomiting that generally improve with continued use; almost all people using setmelanotide experience marked skin darkening due to off-target activation of cutaneous MC1R.

Functional characterization of all missense variants in LEPR, PCSK1, and POMC genes arising from single-nucleotide variants

ABSTRACT Objective Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pathway. In vitro functional characterization of 12,879 possible exonic missense variants from single-nucleotide variants (SNVs) of LEPR, POMC, and PCSK1 was performed to determine the impact of these variants on protein function. Methods SNVs of the three genes were transiently transfected into cell lines, and each variant was subsequently classified according to functional impact. We validated three assays by comparing classifications against functional characterization of 29 previously published variants. Results Our results significantly correlated with previously published pathogenic categories (r = 0.623; P = 3.03 × 10–4) of all potential missense variants arising from SNVs. Of all observed variants identified through available databases and a tested cohort of 16,061 patients with obesity, 8.6% of LEPR, 63.2% of PCSK1, and 10.6% of POMC variants exhibited LOF, including variants currently classified as a variant of uncertain significance (VUS). Conclusions The functional data provided here can assist in the reclassification of several VUS in LEPR, PCSK1, and POMC and highlight their impact in MC4R pathway diseases.

OR10-1 Body Mass Index and Weight Reductions in Patients With Obesity Due to Heterozygous Variants in POMC, PCSK1, and LEPR After 1 Year of Setmelanotide

Abstract Background The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR. Methods Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline. Results As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m2, body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment. Conclusions Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634). Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

ODP605 Body Mass Index and Weight Reductions in Patients With SRC1 Genetic Variant Obesity After 1 Year of Setmelanotide

Abstract Background The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Steroid receptor coactivator 1 (SRC1; also known as NCOA1) is a transcriptional coactivator that regulates proopiomelanocortin (POMC) expression in the MC4R pathway. Certain SRC1 variants impair MC4R signaling and are associated with hyperphagia (pathologic insatiable hunger) and early-onset, severe obesity. Treatment with setmelanotide, an MC4R agonist, resulted in weight and hunger reductions after 3 months in patients with SRC1 variant obesity in a Phase 2 study. This analysis is the first to assess the continued efficacy of 1 year of setmelanotide treatment in patients with SRC1 variant obesity. Methods Patients with SRC1 variant obesity aged ≥6 years were eligible for this long-term extension (LTE) trial (NCT03651765) if they completed an index trial in which they received setmelanotide and demonstrated clinical benefit on the basis of efficacy and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of setmelanotide treatment as part of the index trial and began the LTE immediately following completion. Study visits occurred approximately every 3 months. Study objectives included evaluating changes in weight-related measures and tolerability. The current analysis reports outcomes after 1 year of setmelanotide treatment across the index and LTE trials, relative to index trial baseline. Results As of October 29, 2021, 30 patients (20 ≥18 years old and 10 <18 years old) with SRC1 variant obesity enrolled in the index trial. Seventeen patients entered the LTE; at the time of analysis, 16, 11, and 8 patients had received at least 6, 9, and 12 months of treatment, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all patients was 45.4 (11.3) kg/m2, body weight in patients ≥18 years old was 139.7 (25.1) kg, and BMI Z score in patients <18 years old was 2.99 (0.63). After 6, 9, and 12 months of treatment, mean (SD) percent change in BMI was −5.7% (5.6%; n=16), −7.8% (5.8%; n=11), and −10.1% (9.4%; n=8), respectively. Mean (SD) percent change in body weight in patients ≥18 years old at 6, 9, and 12 months was −6.7% (6.1%; n=11), −9.9% (7.4%; n=8), and −11. 0% (8.6%; n=7), respectively. The mean (SD) change in BMI Z score was −0.35 (0.35; n=7), −0.42 (0.23; n=5), and −0.67 (0.57; n=3) after 6, 9, and 12 months, respectively. No new safety concerns emerged during long-term treatment, and no patients discontinued because of an adverse event. Conclusions One year of setmelanotide treatment led to clinical weight benefits in patients with SRC1 variant obesity. These data support the continued investigation of setmelanotide in this population, which is underway in the Phase 3 EMANATE trial (NCT05093634). Presentation: No date and time listed

RF24 | PSUN96 Setmelanotide in Patients With Heterozygous POMC, LEPR, SRC1, or SH2B1 Obesity: Design of EMANATE – A Placebo-Controlled Phase 3 Trial

Abstract Background The central hypothalamic melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Certain variants in genes upstream of MC4R, including those encoding the leptin receptor (LEPR), proopiomelanocortin (POMC), steroid receptor coactivator 1 (SRC1; also known as NCOA1), prohormone convertase (PC)1/3 (encoded by the gene PCSK1), and SH2B adaptor protein 1 (SH2B1) genes, lead to impaired MC4R pathway signaling and rare genetic diseases of obesity. While the deficiencies resulting from these genetic variants differ in some clinical features, they are all characterized by hyperphagia (pathologic insatiable hunger) and early-onset obesity during childhood. Setmelanotide, an MC4R agonist, reduced body weight and hyperphagia (assessed by hunger scores) after 3 months in patients with heterozygous POMC, including patients with the N221D variant in PCSK1; LEPR; SRC1; and SH2B1 (including a 220–kilobase pair distal deletion of chromosome 16p11.2) variants in an earlier Phase 2 trial. In the Phase 2 trial, 12 of 35 (34%) patients with heterozygous POMC, PCSK1, or LEPR variants; 9 of 30 patients (30%) with heterozygous SRC1 variants; and 13 of 35 (37%) patients with heterozygous SH2B1 variants achieved ≥5% weight loss after 3 months of setmelanotide treatment. Methods EMANATE is a randomized, double-blind, placebo-controlled Phase 3 trial (NCT05093634) comprising 5 similar independent sub-studies based on genetic variants. For eligibility, patients must be 6-65 years old, have history of hyperphagia and childhood obesity, current obesity defined as BMI ≥30 kg/m2 (in those ≥18 years old), and BMI ≥95th percentile (in those 6-17 years old). Patients must also have a heterozygous genetic variant in POMC or PCSK1; heterozygous genetic variant in LEPR; a homozygous, heterozygous, or compound heterozygous variant in SRC1 or SH2B1 (including a chromosomal deletion of 16p11.2 including SH2B1); or a heterozygous N221D variant in PCSK1. Patients with ≥2% weight loss in the prior 3 months, HbA1C >10%, clinically significant pulmonary, cardiac, or oncological disease, or history of significant liver or serious kidney disease are not eligible. Within each sub-study, patients will be randomized 1: 1 to receive daily subcutaneous injections of setmelanotide or placebo for 52 weeks. The primary outcome is the mean change in body weight in patients who receive setmelanotide compared with placebo. Safety will be assessed by frequency and severity of adverse events. Current Status: EMANATE is currently underway and began enrolling patients in early 2022. The planned enrollment is 560 patients. If successful, this placebo-controlled Phase 3 trial will support setmelanotide treatment for improvements in body weight–related measures and hunger in an expanded population of patients living with rare genetic diseases of obesity. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

ODP607 Long-term Efficacy of Setmelanotide in Patients With POMC or LEPR Deficiency Obesity

Abstract The melanocortin-4 receptor (MC4R) pathway in the brain is responsible for energy regulation, affecting appetite and body weight. Impairments of this pathway can result in hyperphagia (insatiable hunger) and obesity. The MC4R can be impacted by the POMC, PCSK1, or LEPR genes. Variants in these genes that are inherited from both parents (biallelic) can result in MC4R pathway signaling deficiencies. Setmelanotide is a drug that activates the MC4R. In earlier Phase 3 studies, setmelanotide was shown to improve hunger and reduce weight in patients with POMC, PCSK1, and LEPR biallelic deficiency. The present study aims to examine the long-term efficacy of ∼3 years of setmelanotide treatment in patients with POMC, PCSK1, and LEPR biallelic deficiency in a long-term extension after a previous trial. Setmelanotide treatment continued to provide sizable reductions in body weight and body mass index while being generally well tolerated. These findings provide strong support of the safe and effective long-term use of setmelanotide to treat obesity in patients with POMC, PCSK1, and LEPR biallelic deficiency. Presentation: No date and time listed

Design of a phase 2, double-Blind, placebo-controlled trial of setmelanotide in patients with genetic variants in the melanocortin-4 receptor pathway

Design of a phase 2, double-Blind, placebo-controlled trial of setmelanotide in patients with genetic variants in the melanocortin-4 receptor pathway

EP126: Frequency of MC4R pathway variants in a large US cohort of pediatric and adult patients with severe obesity

The melanocortin-4 receptor (MC4R) pathway is critical for the regulation of energy balance. Variants in a number of genes within this pathway have well-established associations with severe obesity. However, the overall frequency of rare variants in these genes has not been assessed systematically in a clinically relevant population, and it is unknown whether variant frequency differs depending on the age of ascertainment. Genetic testing can improve diagnosis of rare genetic diseases of obesity and identify patients who may benefit from targeted therapeutic intervention. We sequenced exons and intron-exon boundaries for 40 obesity-related genes in individuals with severe obesity (defined as ≥97th percentile of body mass index [BMI] for age in those <18 years old, or BMI ≥40 kg/m2 in those ≥18 years old) who participated in the US-based Uncovering Rare Obesity diagnostic genetic testing program. This next-generation sequencing panel included 11 genes associated with nonsyndromic obesity that encode proteins functioning in the MC4R pathway (POMC, PCSK1, LEPR, SRC1 [NCOA1], SH2B1, MC4R, MC3R, CPE, LEP, KSR2, and SIM1). Variants were classified as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS) according to American College of Medical Genetics and Genomics criteria. We additionally included 1 nonrare variant, PCSK1 p.N221D, for which published functional and population studies suggests a potential contribution to obesity. Individuals with variants in 5 of these genes (POMC, PCSK1, LEPR, SRC1, and SH2B1) have previously been assessed in a trial using the MC4R agonist setmelanotide and demonstrated meaningful weight loss. Variants were classified according to their classical mode of inheritance (autosomal dominant: SRC1, SH2B1, MC4R, MC3R, KRS2, and SIM1; autosomal recessive: POMC, PCSK1, CPE, and LEP). Among 7,826 individuals, 16%, 33%, 30%, and 21% were aged <6, 6–12, 12–18, and >18 years, respectively. Among these individuals, 19% carried ≥1 rare variant in ≥1 of the 11 studied genes, including 3.6% carrying a P/LP variant and 15.4% carrying a VUS variant. Additionally, 11.9% of individuals had variants in line with mode of inheritance, including 2.1% of individuals with all P/LP variants. Restricting to the 5 genes with prior demonstrated responsiveness to setmelanotide (POMC, PCSK1, LEPR, SRC1, and SH2B1), the variant frequency was 11% for P/LP or VUS variants. An additional 6.4% of individuals carried the PCSK1 p.N221D variant. No differences in frequency were observed by age group. In our large US-based cohort of individuals with early-onset, severe obesity, 25.4% of individuals carried a potentially clinically relevant variant in ≥1 of 11 MC4R pathway–related genes, including 11.9% of individuals with variants in line with classical mode of inheritance. Genetic testing of patients with severe obesity may therefore be an important component of understanding the etiology of these patients’ phenotypes. No differences in variant frequency were observed across age groups, indicating that genetic testing for obesity-related genes is appropriate in both pediatric and adult patients with severe obesity.

EP123: Design of a phase 2, double-blind, placebo-controlled trial of setmelanotide in patients with genetic variants in the melanocortin-4 receptor pathway

Rare genetic causes of obesity include variants in genes within the melanocortin-4 receptor (MC4R) pathway, a principal regulator of energy balance. Weight and hunger reductions following treatment with the MC4R agonist setmelanotide have been demonstrated in patients with obesity due to variants in multiple genes, including POMC, LEPR, SRC1, and SH2B1. We describe the design of DAYBREAK, a Phase 2 trial of setmelanotide in patients with additional specific gene variants based on an evidence-based framework that suggested relevance to the MC4R pathway (ClinicalTrials.gov identifier: NCT04963231).

EP012: Biochemical characterization of single minded-1 missense variants associated with severe obesity

Single Minded-1 (SIM1) is a transcription factor involved in development and function of the hypothalamic paraventricular nucleus, a site critical for the body weight–regulating function of the melanocortin-4 receptor (MC4R) pathway. Consistent with its MC4R pathway involvement, rare loss-of-function (LOF) variants in SIM1 are associated with severe early-onset obesity and hyperphagia, hallmark features of rare genetic diseases of obesity. To better understand the contribution of SIM1 variants to severe clinical obesity, we performed functional biochemical characterization of rare SIM1 variants in Rhythm’s database of approximately 40,000 individuals with severe obesity.

EP124: Uncovering rare obesity genetic testing program: Overview and health care provider utilization

Identification of gene variants associated with rare genetic diseases of obesity may improve clinical care by providing specialized management strategies. The Uncovering Rare Obesity diagnostic genetic testing program aims to enhance genetic testing access. We describe the program design and report utilization patterns to date. The Uncovering Rare Obesity program, launched in May 2019, provides no-charge genetic tests and 2 genetic counseling sessions to individuals in the United States. Eligibility criteria include age ≤18 years with a body mass index (BMI) ≥97th percentile or age ≥19 years with a BMI of ≥40 kg/m2 and a history of childhood obesity before age 10. Select family members of tested individuals are also eligible. As of March 2021, the test screened for variants in 40 genes associated with the melanocortin-4 receptor pathway, which regulates energy balance. Uncovering Rare Obesity test kit (blood, buccal, or saliva) requests and submissions by health care providers (HCPs) were evaluated to determine program utilization. As of March 31, 2021, the Uncovering Rare Obesity program was utilized by HCPs in all 50 states as well as Puerto Rico and the District of Columbia; 1425 unique HCPs submitted 7674 samples for testing (mean 5.4 submissions/HCP). In total, 47% of the requested 16,427 kits have been returned for processing. Kits were requested and submitted by 2261 and 1425 unique HCPs, respectively (63% utilization). The top 10 HCPs utilizing the program submitted an average of 53 tests per month combined. Between October 2020 and March 2021, the monthly average of new HCP Uncovering Rare Obesity program users was 64. The most common specialties of HCPs submitting tests were pediatric endocrinology (34%), pediatrics (23%), and medical genetics (14%). Of patients for whom tests were submitted, 21% were ≤6 years, 57% were 7–17 years, and 23% were ≥18 years; 92% of test results were returned within 4 weeks of submission. The Uncovering Rare Obesity program was highly utilized by HCPs across specialties in diagnosing rare genetic diseases of obesity.

Effects of Setmelanotide in Patients With POMC, PCSK1, or LEPR Heterozygous Deficiency Obesity in a Phase 2 Study

Abstract Introduction: Setmelanotide is a melanocortin 4 receptor (MC4R) agonist being investigated for chronic weight management in patients with rare genetic diseases of obesity caused by impairment of the MC4R pathway. The objective of this analysis was to assess the efficacy and safety of setmelanotide in patients with partial insufficiency in the MC4R pathway due to heterozygous mutations in the POMC, PCSK1, or LEPR genes. Methods: This was an open-label, single-arm, Phase 2 study of setmelanotide in rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) heterozygous deficiency obesity (NCT03013543). Patients aged ≥6 years with POMC, PCSK1, or LEPR heterozygous deficiency obesity received once-daily setmelanotide, which was titrated for 4 weeks to establish the therapeutic dose of 3 mg daily. Treatment at the therapeutic dose continued for an additional 12 weeks. The primary endpoint was mean percent change from baseline in body weight at Month 3. Hunger scores and adverse events (AEs) were secondary endpoints. A responder was defined as having ≥5% weight loss from baseline at Month 3. Results: A total of 35 patients were included in this analysis, with mean (standard deviation) age of 39.5 (17.6) years and body mass index of 50.3 (9.4) kg/m2. Across all patients, the mean percent change in body weight from baseline to Month 3 was −3.7% (90% confidence interval [CI], −5.3% to −2.1%; n=35). A total of 34.3% of patients (12/35) achieved the responder threshold of ≥5% weight loss from baseline at Month 3. The mean percent change in body weight from baseline to Month 3 was −10.1% (90% CI, −12.4% to −7.9%; n=12) and −0.4% (90% CI, −1.2% to −0.5%; n=23) for responders and nonresponders, respectively. The mean percent change in most hunger score from baseline to Month 3 was −4.4% (90% CI, −5.7% to −3.2%; n=10) and −2.3% (90% CI, −3.2% to −1.5%; n=23) for responders and nonresponders, respectively. Among responders, 4 (33%) had variants that were considered pathogenic/likely pathogenic per American College of Medical Genetics criteria. All patients experienced at least 1 AE. Overall, the most common treatment-emergent AEs were skin hyperpigmentation (51.4%), nausea (48.6%), and injection site pruritis (37.8%). One patient had serious AEs of acute myocardial infarction and gastrointestinal hemorrhage that were considered unrelated to setmelanotide. No AEs led to death. Conclusions: Setmelanotide was associated with reduced body weight and hunger scores in patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity. While the overall mean percent decrease in body weight may have been less than that previously reported in patients with homozygous or compound heterozygous variants, setmelanotide may be a viable treatment option for some patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity.

Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials

The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. Rhythm Pharmaceuticals.

1920-P: First Oral MC4R Agonist for the Treatment of Rare Genetic Obesity

Melanocyte-stimulating hormones, neuropeptides induced by Pro-opiomelanocortin (POMC) in the hypothalamus, act as the endogenous ligands of Melanocortin 4 receptor (MC4R). They decrease appetite by MC4R activation, leading to weight loss. Dysfunction of genes in MC4R pathway is known to cause rare genetic obesity such as POMC deficiency, leptin receptor deficiency, Bardet-Biedl syndrome and Alström syndrome. Therefore, MC4R agonists have the potential to be therapeutic agents for such genetic obesities. Compound LB(LB) is an orally available, small molecule MC4R agonist under clinical development. In vitro activity of LB toward MC4R and selectivity over MC1R, MC3R and MC5R were measured by radio-ligand binding, luciferase, cAMP and β-arrestin assays. LB showed a high potency and selectivity toward MC4R. In vivo efficacy of LB was tested in high fat diet-induced obese mice, rats and KK-Ay mice. Following repeat-dose to obese rodents, LB led to appetite suppression and weight loss comparable to or higher than setmelanotide. To evaluate in vivo pharmacokinetic properties, a single dose of LB was administered to mice, rats, dogs and monkeys. The GLP toxicology program of LB was comprised of general toxicity studies in rats and monkeys up to 4 weeks, genotoxicity and safety pharmacology studies. The IND-enabling toxicology studies demonstrated good safety profiles in the rats and monkeys. LB showed no significant safety issue in the genotoxicity and safety pharmacology studies. Comprehensive in vitro and in vivo studies demonstrated that LB is potent and selective MC4R agonist. LB is safe and well-tolerated compound, as demonstrated in GLP toxicity studies. In addition, the observed efficacy and safety profiles of LB are well described by the preclinical pharmacokinetic properties of LB such as a great penetration to brain tissue. In conclusion, these nonclinical studies suggested that LB can be a safe and effective drug for the patients with genetic obesity. Disclosure H. Park: None. S. Yeo: None. H. Park: Employee; Self; LG Chem. J. Park: None. P.S. Hong: None.